Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein secreted by macrophages, fibroblasts, and endothelial cells originally identified by its ability to stimulate the survival, proliferation, and differentiation in vitro of predominantly neutrophilic granulocytes from bone marrow progenitors. Nicola, N. A., Annu. Rev. Biochem. (1989) 58:45. The capacity of G-CSF to regulate in vivo granulopoiesis is supported by animal and clinical studies, which demonstrated a reversible rise in circulating neutrophil levels in response to administered recombinant G-CSF. Gabrilove, J. L. et al., N. Engl. J. Med. (1988) 318:1414. G-CSF has pleiotropic effects on mature neutrophils, enhancing their survival and stimulating functional activation, including induction of neutrophil alkaline phosphatase (Sato. N. et al., J. Cell. Physiol. (1988) 37:272) and high affinity IgA Fc receptors (Weisbart, R. H., et al., Nature (Lond.) (1988) 332:647), priming for respiratory burst (Nathan, C. F. Blood (1989) 73:301) and increased chemotaxis (Wang, J. M., Blood (1988) 72:1456). G-CSF effects have also been observed on hematopoietic cells that are not committed to the granulocyte lineage, for example, stimulation of the proliferation on monocytic differentiation in vitro of some myeloid leukemic cells (Geissler, K., J. Immunol. (1989) 143:140) and the proliferation in vitro of some multipotential hematopoietic precursors (Ferrero, D., Blood (1989) 73:402).
Administration of recombinant G-CSF to patients suffering from neutropenia due to various causes indicated that G-CSF is beneficial as an adjuvant in chemotherapy and in bone marrow transplantation (Morstyn, G., et al., Trends Pharmacol. Sci. 10, (1989) 154-159). G-CSF activity is also associated with mobilization of hematopoietic stem cells from the marrow to the peripheral blood. (See review article, Good Review article Haylock et al., Blood 89:2233-2258, 1997).
It would be desirable to provide compounds which allow for the treatment of neutropenia to enhance leukocyte production by acting as a G-CSF mimetics.
As disclosed herein it has unexpectedly been discovered that certain octacyclic compounds are effective as G-CSF mimetics.
This invention relates to compounds of Formula (1): 
wherein R1 and R2 are independently aryl,
where aryl is cyclic or polycyclic aromatic C3-C12, optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms, and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: C(O)NR11R12, NR11R12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C6-C12aryl, alkoxy, acyloxy, substituted C6-C12aryl, trifluoromethyl, methoxycarbonyl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, xe2x80x94C(O)OR11, xe2x80x94S(O)2NR11R12, xe2x80x94S(O)nR13, protected xe2x80x94OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-C12aryl, substituted C6-C12aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, xe2x80x94C(O)OR11, xe2x80x94S(O)2NR11R12, xe2x80x94S(O)nR13, aryloxy, nitro, cyano, halogen and protected xe2x80x94OH, where
R11 and R12 are independently hydrogen, cycloalkyl, C6-C12aryl, substituted cycloalkyl, substituted C6-C12aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, xe2x80x94C(O)OR13, xe2x80x94S(O)nR13, C(O)N(R13)2, S(O)2N(R13)2, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C6-C12aryl, substituted C6-C12aryl and protected xe2x80x94OH,
n is 0-2,
R13 is hydrogen, alkyl, cycloalkyl, C6-C12aryl, substituted alkyl, substituted cycloalkyl and substituted C6-C12aryl;
R3, R4, R5, R6, R7, R8, R9 and R10 are independently hydrogen, C(O)NR11R12, NR11R12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C6-C12aryl, alkoxy, acyloxy, substituted C6-C12aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, xe2x80x94C(O)OR11, xe2x80x94S(O)2NR11R12, xe2x80x94S(O)nR13, protected xe2x80x94OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-C12aryl, substituted C6-C12aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, xe2x80x94C(O)OR11, xe2x80x94S(O)2NR11R12, xe2x80x94S(O)nR13, aryloxy, nitro, cyano, halogen and protected xe2x80x94OH, where R11, n, R12 and R13 are as described above;
X is O, S or NR11,
where R11 is as described above; and
Y is O or S; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
The present invention also relates to the discovery that the compounds of Formula (I) are active as G-CSF mimetics.
The invention also is a method for treating neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production in mammals, including humans, which comprises administering to a subject in need thereof an effective amount of a presently invented G-CSF mimetics compound.
The invention is also a method for treating bacterial and fungal infections in mammals, including humans, which comprises administering to a subject in need thereof an effective amount of a presently invented G-CSF mimetics compound.
In a further aspect of the invention there is provided novel processes useful in preparing the presently invented G-CSF mimetics compounds.
Included in the present invention are pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention.
Also included in the present invention are methods of co-administering the presently invented G-CSF mimetics compounds with further active ingredients.
The compounds of this invention that act as G-CSF mimetics have the following Formula (1): 
wherein R1 and R2 are independently aryl,
where aryl is cyclic or polycyclic aromatic C3-C12, optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms, and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: C(O)NR11R12, NR11R12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C6-C12aryl, alkoxy, acyloxy, substituted C6-C12aryl, trifluoromethyl, methoxycarbonyl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, xe2x80x94C(O)OR11, xe2x80x94S(O)2NR11R12, xe2x80x94S(O)nR13, protected xe2x80x94OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-C12aryl, substituted C6-C12aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, xe2x80x94C(O)OR11, xe2x80x94S(O)2NR11R12, xe2x80x94S(O)nR13, aryloxy, nitro, cyano, halogen and protected xe2x80x94OH, where
R11 and R12 are independently hydrogen, cycloalkyl, C6-C12aryl, substituted cycloalkyl, substituted C6-C12aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, xe2x80x94C(O)OR13, xe2x80x94S(O)nR13, C(O)N(R13)2, S(O)2N(R13 )2, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C6-C12aryl, substituted C6-C12aryl and protected xe2x80x94OH,
n is 0-2,
R13 is hydrogen, alkyl, cycloalkyl, C6-C12aryl, substituted alkyl, substituted cycloalkyl and substituted C6-C12aryl;
R3, R4, R5, R6, R7, R8, R9 and R10 are independently hydrogen, C(O)NR11R12, NR11R12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C6-C12aryl, alkoxy, acyloxy, substituted C6-C12aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, xe2x80x94C(O)OR11, xe2x80x94S(O)2NR11R12, xe2x80x94S(O)nR13, protected xe2x80x94OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-C12aryl, substituted C6-C12aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, xe2x80x94C(O)OR11, xe2x80x94S(O)2NR11 R12, xe2x80x94S(O)nR13, aryloxy, nitro, cyano, halogen and protected xe2x80x94OH, where R11, n, R12 and R13 are as described above;
X is O, S or NR11,
where R11 is as described above; and
Y is O or S; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
Preferred among the presently invented Formula I compounds are those in which aryl is: C5-C12aryl, optionally containing one or two heteroatoms and optionally substituted with one or more substituents selected from the group consisting of: xe2x80x94OC6-C12aryl, xe2x80x94(CH2)mOH, C6-C12aryl, C1-C4alkyl,xe2x80x94OC1 -C4alkyl, amino, nitro, cyano, methoxycarbonyl, N-acylamino, trifluoromethyl, C3-7cycloalkyl, halogen, xe2x80x94(CH2)pCOOH, xe2x80x94S(O)nR13 and protected xe2x80x94OH, where m is 0-4, p is 0-3, n is 0-2 and R13 is hydrogen or C1-4alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
Particularly preferred among the presently invented compounds are those in which R1 and R2 are independently phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl or quinolyl all of which are unsubstituted or substituted with a substituent selected from the group consisting of: halogen, C1-5alkyl, trifluoromethyl, xe2x80x94COOH, methoxycarbonyl, C3-7cycloalkyl and xe2x80x94Oxe2x80x94C1-4alkyl;
R3, R4, R5, R6, R7, R8, R9 and R10 are independently hydrogen, xe2x80x94OC6-C12aryl, C6-C12aryl, C1-C4alkyl,xe2x80x94OC1-C4alkyl, amino, nitro, cyano, N-acylamino, C3-7cycloalkyl, halogen, xe2x80x94S(O)nR13 or protected xe2x80x94OH, where m is 0-4, p is 0-3, n is 0-2 and R13 is hydrogen or C1-4alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
Particularly preferred among the presently invented compounds are those in which R1 and R2 are independently phenyl, furyl, thienyl or pyridyl all of which are unsubstituted or substituted with a substituent selected from the group consisting of: halogen, C1-5alkyl, trifluoromethyl, xe2x80x94COOH, methoxycarbonyl, C3-6cycloalkyl and xe2x80x94Oxe2x80x94C1-3alkyl;
R3, R4, R5, R6, R7, R8, R9 and R10 are independently hydrogen, halogen, C1-5alkyl, C3-7cycloallyl or xe2x80x94Oxe2x80x94C1-4alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
The most preferred compounds of the present invention are those in which R1 and R2 are independently phenyl, furyl or pyridyl all of which are unsubstituted or substituted with a substituent selected from the group consisting of: halogen, C1-5alkyl, trifluoromethyl, xe2x80x94COOH, methoxycarbonyl and xe2x80x94Oxe2x80x94C1-3alkyl; and
R3, R4, R5, R6, R7, R8, R9 and R10 are independently hydrogen, trifluoromethyl, methoxycarbonyl, halogen or C1-3alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
Preferred among the presently invented compounds are:
Compound A; 7a, 17a-bis(2-pyridyl)-16,19-dioxo-5,7a, 10,16,17a, 19-hexahydro-benzimidazo[2xe2x80x2,1xe2x80x2:4,5][1,3,5]triazino[1,2-a]benzimidazo[2xe2x80x3,1xe2x80x3:4xe2x80x2,5xe2x80x2][1,3,5]triazino[1xe2x80x2,2xe2x80x2:1,2]imidazo[4,5-d]imidazole;
Compound B; 16,19-dioxo-7a, 17a-diphenyl-5,7a, 10,16,17a, 19-hexahydro-benzimidazo[2xe2x80x2,1xe2x80x2:4,5][1,3,5]triazino[1,2-a]benzimidazo[2xe2x80x3,1:4xe2x80x2,5xe2x80x2][1,3,5]triazino[1xe2x80x2,2xe2x80x2:1,2]imidazo[4,5-d]imidazole;
Compound E; 7a, 17a-bis(4-fluorophenyl)- 16,19-dioxo-5,7a, 10,16,1 7a, 19-hexahydro-benzimidazo[2xe2x80x2,1xe2x80x2:4,5][1,3,5]triazino[1,2-a]benzimidazo[2xe2x80x3,1xe2x80x3:4xe2x80x2,5xe2x80x2][1,3,5]triazino[1xe2x80x2,2xe2x80x2:1,2]imidazo[4,5-d]imidiazole;
Compound G; 7a, 17a-bis(3-methoxyphenyl)- 16,19-dioxo-5,7a, 10,16,1 7a, 19-hexahydro-benzimidazo[2xe2x80x2,1xe2x80x2:4,5][1,3,5]triazino[1,2-a]benzimidazo[2xe2x80x3,1xe2x80x3:4xe2x80x2,5xe2x80x2][1,3,5]triazino[1xe2x80x2,2xe2x80x2:1,2]imidazo[4,5-d]imidazole;
Compound H; 3,12-dinitro-16,19-dioxo-7a, 17a-diphenyl-5,7a, 10,16,17a, 19-hexahydro-benzimidazo[2xe2x80x2,1xe2x80x2:4,5][1,3,5]triazino[1,2-a]benzimidazo[2xe2x80x3,1xe2x80x3:4xe2x80x2,5xe2x80x2][1,3,5]triazino[1xe2x80x2,2xe2x80x2:1,2]imidazo[4,5-d]imidazole;
Compound I; 2,12-dinitro- 16,19-dioxo-7a, 17a-diphenyl-5,7a, 10,16,17a, 19-hexahydro-benzimidazo[2xe2x80x2,1xe2x80x2:4,5][1,3,5]triazino[1,2-a]benzimidazo[2xe2x80x3,1xe2x80x3:4xe2x80x2,5xe2x80x2][1,3,5]triazino[1xe2x80x2,2xe2x80x2:1,2]imidazo[4,5-d]imidazole imidazole;
Compound J; 2,13-dinitro-16,19-dioxo-7a, 17a-diphenyl-5,7a, 10,16,17a, 19-hexahydro-benzimidazo[2xe2x80x2,1xe2x80x2:4,5][1,3,5]triazino[1,2-a]benzimidazo[2xe2x80x3,1xe2x80x3:4xe2x80x2,5xe2x80x3][1,3,5]triazino[2xe2x80x2:1,2]imidazo[4,5-d]imidazole imidazole and
pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
By the term xe2x80x9cprotected hydroxyxe2x80x9d or xe2x80x9cprotected xe2x80x94OHxe2x80x9d as used herein, is meant the alcoholic or carboxylic xe2x80x94OH groups which can be protected by conventional blocking groups in the art as described in xe2x80x9cProtective Groups In Organic Synthesisxe2x80x9d by Theodora W. Greene, Wiley-Interscience, 1981, New York.
By the term xe2x80x9cC5-C12 arylxe2x80x9d as used herein, unless otherwise defined, is meant a cyclic or polycyclic aromatic C5-C12 optionally containing one or two heteroatoms.
By the term xe2x80x9cC6-C12 arylxe2x80x9d as used herein, unless otherwise defined, is meant phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl, or biphenyl.
By the term xe2x80x9csubstitutedxe2x80x9d as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of: hydroxyalkyl, alkoxy, acyloxy, alkyl, amino, N-acylamino, hydroxy, xe2x80x94(CH2)gC(O)OR11, xe2x80x94S(O)2NR11R12, xe2x80x94S(O)nR12, nitro, cyano, halogen, trifluoromethyl and protected xe2x80x94OH, where g is 0-6, R11 is hydrogen or alkyl, n is 0-2, and R12 is hydrogen or alkyl.
By the term xe2x80x9calkoxyxe2x80x9d as used herein is meant xe2x80x94Oalkyl where alkyl is as described herein including xe2x80x94OCH3 and xe2x80x94OC(CH3)2CH3.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12 
Examples of cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl 4-methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl and cyclopentyl.
By the term xe2x80x9cacyloxyxe2x80x9d as used herein is meant xe2x80x94OC(O)alkyl where alkyl is as described herein. Examples of acyloxy substituents as used herein include: xe2x80x94OC(O)CH3, xe2x80x94OC(O)CH(CH3)2 and xe2x80x94OC(O)(CH2)3CH3.
By the term xe2x80x9cN-acylaminoxe2x80x9d as used herein is meant xe2x80x94N(H)C(O)alkyl, where alkyl is as described herein. Examples of N-acylamino substituents as used herein include: xe2x80x94N(H)C(O)CH3, xe2x80x94N(H)C(O)CH(CH3)2 and xe2x80x94N(H)C(O)(CH2)3CH3.
By the term xe2x80x9caryloxyxe2x80x9d as used herein is meant xe2x80x94OC6-C12aryl where C6-C12aryl is phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphenyl optionally substituted with one or more substituents selected from the group consisting of: alkyl, hydroxyalkyl, alkoxy, trifuloromethyl, acyloxy, amino, N-acylamino, hydroxy, xe2x80x94(CH2)gC(O)OR11, xe2x80x94S(O)nR12, nitro, cyano, halogen and protected xe2x80x94OH, where g is 0-6, R11 is hydrogen or alkyl, n is 0-2 and R12 is hydrogen or alkyl. Examples of aryloxy substituents as used herein include: phenoxy, 4-fluorophenyloxy and biphenyloxy.
By the term xe2x80x9cheteroatomxe2x80x9d as used herein is meant oxygen, nitrogen or sulfur.
By the term xe2x80x9chalogenxe2x80x9d as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride.
By the term xe2x80x9calkylxe2x80x9d and derivatives thereof and in all carbon chains as used herein is meant a linear or branched, saturated or unsaturated hydrocarbon chain having C1-C12 carbon atoms. Examples of alkyl substituents as used herein include: xe2x80x94CH3, xe2x80x94CH2xe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH3, xe2x80x94CH(CH3)2, xe2x80x94C(CH3)3, xe2x80x94(CH2) xe2x80x94CH2xe2x80x94CH(CH3)2 and xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94CH3, xe2x80x94CHxe2x95x90CH2.
By the term xe2x80x9ctreatingxe2x80x9d and derivatives thereof as used herein, is meant prophylatic or therapeutic therapy.
By the phrase xe2x80x9cmobilizing peripheral blood stem cellsxe2x80x9d as used herein is meant the mobilization of hematopoietic stem cells from the marrow to the peripheral blood.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
Compounds of Formula (1) are included in the pharmaceutical compositions of the invention and used in the methods of the invention. Where a xe2x80x94COOH or xe2x80x94OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for xe2x80x94COOH, and acetate maleate and the like for xe2x80x94OH, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
By the term xe2x80x9cco-administeringxe2x80x9d and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a G-CSF mimetic compound, as described herein, and a further active ingredient or ingredients, such as antibacterial agents, antifungal agents as well as agents known to treat neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compounds may be administered orally.
The novel compounds of Formula (I) are prepared as shown in Scheme I below provided that the xe2x80x98Rxe2x80x99, X and Y substituents do not include any such substituents that render inoperative the Scheme I process. The compounds of Formula (2) are prepared by methods analogous to the Schemes and Examples used to prepare the Formula (I) compounds in International Application PCT/US97/08864, Published on Nov. 27, 1997 as WO 97/44033. The reagents used herein are commercially available or are readily made by those skilled in the art from commercially available materials. 
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and X are as described in Formula (I) above, are reacted with phosgene or thiophosgene or an appropriate phosgene or thiophosgene equivalent such as bistrichloromethyl carbonate, disuccinidimoyl carbonate, carbonyl diimidazole or thiocarbonyl dimidazole in an appropriate solvent, preferably pyridine or 1,2-dichloroethane, to afford octacyclic compounds of Formula (1), 
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Y and X are as described in Formula (1) above; or a mixture comprising a compound of Formula (1) and a compound of Formula (3) 
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Y and X are as described in Formula (1) above. The mixtures of compounds of Formulas (1) and (3) are readily separated by chromatography.
Pharmaceutically acceptable salts, hydrates and solvates are formed when appropriate by methods well known to those of skill in the art.
Because the pharmaceutically active compounds of the present invention are active as G-CSF mimetics they exhibit therapeutic utility in treating bacterial infections, fungal infections, neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production.
In determining potency as G-CSF mimetics, the following assay is employed: CFU-g Assay
The compounds of present invention are tested for potency as G-CSF mimetics in a CFU-g assay, an example of which is described in King AG, Talmadge J., Badger AM, Pelus LM. Regulation of colony stimulating activity production from bone marrow stromal cells by the hematoregulatory peptide, HP-5. Exp. Hematol. 20:223-228, 1992.
The pharmaceutically active compounds within the scope of this invention are useful as G-CSF mimetics in mammals, including humans, in need thereof.
The compound of Example 1 showed activation as indicated in Table 1.
The present invention therefore provides a method of treating bacterial infections, fungal infections, neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production, which comprises administering a compound of Formula (1): 
wherein R1 and R2 are independently aryl,
where aryl is cyclic or polycyclic aromatic C3-C12, optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms, and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: C(O)NR11R12, NR11R12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C6-C12aryl, alkoxy, acyloxy, substituted C6-C12aryl, trifluoromethyl, methoxycarbonyl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, xe2x80x94C(O)OR11, xe2x80x94S(O)2NR11R12, xe2x80x94S(O)nR13, protected xe2x80x94OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-C12aryl, substituted C6-C12aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, xe2x80x94C(O)OR11, xe2x80x94S(O)2NR11 R12, xe2x80x94S(O)nR13, aryloxy, nitro, cyano, halogen and protected xe2x80x94OH, where
R11 and R12 are independently hydrogen, cycloalkyl, C6-C12aryl, substituted cycloalkyl, substituted C6-C12aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, xe2x80x94C(O)OR13, xe2x80x94S(O)nR13, C(O)N(R13)2, S(O)2N(R11)2, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C6-C12aryl, substituted C6-C12aryl and protected xe2x80x94OH,
n is 0-2,
R13 is hydrogen, alkyl, cycoalkyl, C6-C12aryl, substituted alkyl, substituted cycloalkyl and substituted C6-C12aryl;
R3, R4, R5, R6, R7, R8, R9 and R10 are independently hydrogen, C(O)NR11R12, NR11R12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C6-C12aryl, alkoxy, acyloxy, substituted C6-C12aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, xe2x80x94C(O)OR11, xe2x80x94S(O)2NR11R12, xe2x80x94S(O)nR13, protected xe2x80x94OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-C12aryl, substituted C6-C12aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, xe2x80x94C(O)OR11, xe2x80x94S(O)2NR11R12, xe2x80x94S(O)nR13, aryloxy, nitro, cyano, halogen and protected xe2x80x94OH, where R11, n, R12 and R13 are as described above;
X is O, S or NR11,
where R11 is as described above; and
Y is O or S; and
pharmaceutically acceptable salts, hydrates, solvates and esters thereof in a quantity effective to enhance leukocyte production. The compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as G-CSF mimetics. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral.
The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001-100 mg/kg of active compound, preferably 0.001-50 mg/kg. When treating a human patient in need of a G-CSF mimetic, the selected dose is administered preferably from 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg, preferably 0.1 to 350 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular G-CSF mimetic in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
The method of this invention of inducing G-CSF mimetic activity in mammals, including humans, comprises administering to a subject in need of such activity an effective amount of of a presently invented G-CSF mimetic compound.
The invention also provides for the use of a compound of Formula (1) in the manufacture of a medicament for use as a G-CSF mimetic.
The invention also provides for the use of a compound of Formula (1) in the manufacture of a medicament for use in therapy.
The invention also provides for the use of a compound of Formula (1) in the manufacture of a medicament for use in enhancing leukocyte production.
The invention also provides for the use of a compound of Formula (1) in the manufacture of a medicament for use in treating bacterial and fungal infections.
The invention also provides for a pharmaceutical composition for use as a G-CSF mimetic which comprises a compound of Formula (1) and a pharmaceutically acceptable carrier.
The invention also provides for a pharmaceutical composition for use in the treatment of neutropenia which comprises a compound of Formula (1) and a pharmaceutically acceptable carrier.
The invention also provides for a pharmaceutical composition for use in enhancing leukocyte production which comprises a compound of Formula (1)I and a pharmaceutically acceptable carrier.
The invention also provides for a pharmaceutical composition for use in treating bacterial infections which comprises a compound of Formula (1) and a pharmaceutically acceptable carrier.
The invention also provides for a pharmaceutical composition for use in treating fungal infections which comprises a compound of Formula (1) and a pharmaceutically acceptable carrier.
The invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula (1) which comprises bringing the compound of Formula (1) into association with the pharmaceutically acceptable carrier or diluent.
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat bacterial infections, fungal infections, neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production, or compounds known to have utility when used in combination with a G-CSF mimetic or agents known to have utility when used in combination with such G-CSF mimetics.